830346-53-7

Basic information

• Product Name: tert-butyl {(1R)-2-[3-(2,6-difluorobenzyl)-5-(2-fluoro-3-methoxyphenyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl]-1-phenylethyl}carbamate
• CAS NO: 830346-53-7
• Molecular Formula: C₃₂H₃₂F₃N₃O₅
• Molecular Weight: 595.6088
• Mol File: 830346-53-7.mol
• Article Data: 5

Chemical Properties

• Density: 1.284g/cm³
• Refractive Index: 1.572
• CAS DataBase Reference: tert-butyl {(1R)-2-[3-(2,6-difluorobenzyl)-5-(2-fluoro-3-methoxyphenyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl]-1-phenylethyl}carbamate(CAS DataBase Reference)
• NIST Chemistry Reference: tert-butyl {(1R)-2-[3-(2,6-difluorobenzyl)-5-(2-fluoro-3-methoxyphenyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl]-1-phenylethyl}carbamate(830346-53-7)
• EPA Substance Registry System: tert-butyl {(1R)-2-[3-(2,6-difluorobenzyl)-5-(2-fluoro-3-methoxyphenyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl]-1-phenylethyl}carbamate(830346-53-7)

Safety Data

• Hazardous Substances Data: 830346-53-7(Hazardous Substances Data)

Upstream product

• 352303-67-4 (2-fluoro-3-methoxyphenyl)boronic acid 
• 352303-69-6 {(R)-2-[5-bromo-3-(2,6-difluoro-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethyl}-carbamic acid tert-butyl ester 
• 352290-60-9 [3H]-NBI-42902 
• 24424-99-5 di-tert-butyl dicarbonate 
• 67341-01-9 (R)-N-(tert-butoxycarbonyl)phenylglycinol 
• 352303-66-3 5-bromo-1-(2,6-difluoro-benzyl)-6-methyl-1H-pyrimidine-2,4-dione 

Downstream Products

• 830346-54-8 3-[2(R)-(tert-butoxycarbonylamino)-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6-methylthiobenzyl]-6-methylpyrimidine-2,4(1H,3H)-dione 
• 352290-60-9 [3H]-NBI-42902 

Relevant articles and documents

Discovery of sodium R-(+)-4-{2-[5-(2-Fluoro-3-methoxyphenyl)-3-(2-fluoro-6- [trifluoromethyl]-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl] -1-phenylethylamino}butyrate (elagolix), a potent and orally available nonpeptide antagonist of the human gonadotropin-releasing hormone receptor

The discovery of novel uracil phenylethylamines bearing a butyric acid as potent human gonadotropin-releasing hormone receptor (hGnRH-R) antagonists is described. A major focus of this optimization was to improve the CYP3A4 inhibition liability of these uracils while maintaining their GnRH-R potency. R-4-{2-[5-(2-Fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl) -4-methyl-2,6-dioxo-3,6-dihy-dro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyric acid sodium salt, 10b (elagolix), was identified as a potent and selective hGnRH-R antagonist. Oral administration of 10b suppressed luteinizing hormone in castrated macaques. These efforts led to the identification of 10b as a clinical compound for the treatment of endometriosis.

PYRIMIDINE-2,4-DIONE DERIVATIVES AS GONADOTROPIN-RELEASING HORMONE RECEPTOR ANTAGONISTS

GnRH receptor antagonists are disclosed that have utility in the treatment of a variety of sex-hormone related conditions in both men and women. The compounds of this invention have the structure formula (I) wherein R1a, R1b, R2a, R2b, R3, R4, R5, R6, R7 and X are as defined herein, including stereoisomers, prodrugs and pharmaceutically acceptable salts thereof. Also disclosed are compositions containing a compound of this invention in combination with a pharmaceutically acceptable carrier, as well as methods relating to the use thereof for antagonizing gonadotropin-releasing hormone in a subject in need thereof.

3-[(2R)-amino-2-phenylethyl]-1-(2,6-difluorobenzyl)-5-(2-fluoro-3- methoxyphenyl)-6-methylpyrimidin-2,4-dione (NBI 42902) as a potent and orally active antagonist of the human gonadotropin-releasing hormone receptor. Design, synthesis, and in vitro and in vivo characterization

Further structure-activity relationship studies of a series of substituted uracils at the 1, 3, and 5 positions resulted in the discovery of several potent antagonists of the human gonadotropin-releasing hormone receptor. Uracils bearing a side chain derived from phenylglycinol at the 3-position were shown to be orally bioavailable in monkeys. 3-[(2R)-Amino-2-phenylethyl]-1-(2,6- difluorobenzyl)-5-(2-fluoro-3-methoxyphenyl)-6-methylpyrimidin-2,4-di-one (R-13b, NBI 42902) displayed subnanomolar binding affinity (Ki = 0.56 nM) and was a potent functional antagonist (IC50 = 3.0 nM in Ca 2+ flux assay) at the human GnRH receptor. It also bound to the monkey GnRH receptor with high affinity (Ki = 3.9 nM). In addition, R-13b had good plasma exposure in cynomolgus monkeys after oral administration, with a Cmax of 737 ng/mL and an AUC of 2392 ng/mL·h at a 10 mg/kg dose. Moreover, oral administration of R-13b to castrated male cynomolgus monkeys resulted in a significant decrease in serum levels of luteinizing hormone. These results demonstrate that compounds from this series of uracils are potent GnRH antagonists with good oral bioavailability and efficacy in nonhuman primates.